MEDICINE
REVIEW ARTICLE
Targeted Vaccine Selection in Influenza Vaccination Peter Wutzler, Roland Hardt, Markus Knuf, Klaus Wahle
SUMMARY Background: The main target groups for influenza vaccination are the elderly, the chronically ill, infants, and toddlers. Influenza vaccines are needed that suit the immunological particularities of each of these age and risk groups. Recent years have seen the approval of influenza vaccines that are more immunogenic than before, but whose use in Germany is limited by the restriction of reimbursement to a small number of vaccines. Methods: The Medline database was selectively searched for pertinent literature. Results: The suboptimal immunogenicity of conventional influenza vaccines that contain inactivated viral cleavage products and subunits can be markedly improved by the use of squalene-based adjuvant systems, by the integration of viral antigens in virosomal particles, or by intradermal administration. The vaccination of elderly persons with a vaccine containing the adjuvant MF59 was found to lower the risk of hospitalization for influenza or pneumonia by 25% compared to vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the adjuvant ASO3 was found to be associated with an up to 17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a virosomal vaccine lowered the frequency of laboratoryconfirmed influenza in vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%). Conclusion: The newer vaccines possess improved efficacy when used for primary and booster immunization in certain age and risk groups, and they are superior in this respect to conventional vaccines based on viral cleavage products and subunits. The risk/benefit profiles of all currently available vaccines vary depending on the age group or risk group in which they are used. ►Cite this as: Wutzler P, Hardt R, Knuf M, Wahle K: Targeted vaccine selection in influenza vaccination. Dtsch Arztebl Int 2013; 110(47): 793–8. DOI: 10.3238/arztebl.2013.0793
easonal influenza vaccination is recommended in Germany as a standard procedure for all persons aged 60 and above. Moreover, vaccination is also recommended for all persons at elevated risk of serious disease, for pregnant women, and for persons exposed to a higher than usual risk of infection (e1). In April 2012, the Strategic Advisory Group of Experts (SAGE) on Immunization of the World Health Organization (WHO) recommended the extension of national vaccination recommendations to children aged 6 to 59 months. Thus, the spectrum of target groups ranges from infants to very old persons, and from healthy persons with intact immune systems to the chronically ill. There is a corresponding variety in the tasks that influenza vaccines are required to fulfill. For example, a naive immune system that has never yet been in contact with influenza virus antigens cannot be effectively stimulated by the highly purified antigens contained in conventional influenza vaccines. The generation of robust immunity after primary vaccination requires a suitable vaccine, for example, one with added adjuvant or one containing live, attenuated virus (1). The elderly have a less effective immune system that has become accustomed to influenza virus antigens through decades of exposure to naturally occurring viruses and repeated immunizations. They therefore need a strong, age-specific immunologic stimulus to achieve lasting protection against disease due to infection with currently circulating influenza viruses. The same is true of influenza vaccines for the chronically ill. A number of influenza vaccines with improved immunogenicity have been approved in the last few years, and others are currently being clinically tested. In this article, we present the clinically relevant differences between conventional and newer influenza vaccines for each of the target groups in which they are used, and we discuss their optimal application.
S
Methods Institute of Virology and Antiviral Therapy – University Hospital Jena: Prof. Dr. med. habil. Wutzler Catholic Clinic Mainz, St. Hildegardis Hospital: Prof. Dr. med. Hardt Department of Child and Adolescent Medicine, Dr. Horst Schmidt Clinic GmbH, Wiesbaden: Prof. Dr. med. Knuf German Association of General Practitioners, Münster: Prof. Dr. med. Wahle
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47): 793–8
This review is based on a search in the Medline database for publications that appeared from January 2000 to February 2013 and that included the search terms “influenza vaccine,” “immunogenicity,” “efficacy,” and “effectiveness.” Particular emphasis was laid on randomized, controlled trials and meta-analyses.
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Classes of vaccines The influenza viruses that are needed for antigen production in the manufacturing process of the currently approved seasonal, pandemic, and pre-pandemic vaccines are replicated either in incubated hen’s eggs (egg-based influenza vaccines) or in permanent cell lines (cell-based influenza vaccines, made with the use of Madin-Darby canine kidney cells [MDCK] or Vero simian kidney cells). These viruses for vaccination, once they have been inactivated with formaldehyde or β-propiolactone and then purified in a multistep process, can either be incorporated whole into a vaccine (whole-virus vaccines) or else used for the extraction of the viral hemagglutinin surface glycoprotein (HA). Depending on the intensity of the purification steps that follow, the final product is designated as either a splitvirus vaccine or a subunit vaccine (Table 1). Split-virus vaccines contain larger amounts of other viral components than subunit vaccines, which have been subjected to more intense purification. These additional components, however, are neither characterized nor quantified. The more intensely a viral preparation has been purified, the better tolerated it will be when administered, but at the cost of lower immunogenicity (e2). Both split-virus and subunit antigens can be incorporated in virosomal particles (virosomal influenza vaccines) or given in combination with adjuvant systems (adjuvanted influenza vaccines) (Table 1). Whole-virus vaccines are generally formulated without adjuvant. Seasonal trivalent inactivated vaccines (TIV) contain antigens of subtypes A/H1N1, A/H3N2, and B-strain. In Germany, in March 2013, the first quadrivalent inactivated vaccine (QIV) against influenza was approved, containing the HA antigens of the two different genetic lines of influenza B viruses (Victoria and Yamagata) (2, e3). Inactivated influenza vaccines for protection against zoonotic (“pre-pandemic”) or pandemic influenza viruses contain only the antigen of a single, relevant viral strain and are therefore called monovalent inactivated influenza vaccines. The alternative to inactivated vaccines is represented by live attenuated influenza vaccines (LAIV), which, like the inactivated vaccines, are produced in incubated eggs—in this case, in eggs that have been very thoroughly tested for contaminating foreign material (specific-pathogen-free or SPF eggs). LAIV have been approved in trivalent (EU, USA) and quadrivalent (USA) varieties. The efficacy of influenza vaccines depends to a large degree on the correspondence between the viral strains incorporated in the seasonal vaccine and the influenza viruses that are actually circulating during the current season (e4).
Vaccines with improved efficacy TIV with increased antigen content For healthy adults and older children, the efficacy of conventional TIV in the prevention of laboratoryconfirmed influenza infection is well documented (e5,
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e6). Nonetheless, for persons at increased risk, elderly persons, and children under 8 years of age, the efficacy of these vaccines is moderate at best (e5–e8). For children under 2 years of age, a TIV was not found to be any more effective than placebo (e5). Multiple studies have shown that raising the antigen dose from 15 to 60 µg HA increases the immunogenicity of TIV, in the sense of elevating the concentration of antibodies measured in the hemagglutination inhibition test (3–5). On the other hand, the higher antigen dose is also associated with a higher frequency of moderate to severe local and systemic reactions, of which the most common types are pain (5% versus 0%) and myalgia (7% versus 1%) (4). A TIV of this type was approved in the USA in 2009 for use in persons aged 65 and above (6). A comprehensive phase IIIb trial of this high-dose vaccine was carried out during the 2009/2010 influenza season but did not yield any conclusion about its clinical efficacy, as the strain of virus for which the vaccine was designed was strongly divergent from the H1N1 pandemic virus that prevailed at that time (e9). It remains an open question whether the currently approved non-adjuvanted TIV with higher antigen doses are suitable for the primary immunization of immunologically naive persons. Evidence that this may be the case comes from a prospective cohort study carried out in Finland, where small children are given two adult doses of 15 µg HA at a 4-week interval for primary immunization (this is not the practice in other countries) (7). Adjuvanted trivalent influenza vaccines Extensive studies of candidate pandemic vaccines have clearly shown the superiority of adjuvanted vaccines over conventional ones for inducing immunity to the vaccine antigens (8, e10). This holds both for primary immunization of the naive immune system and for boosters to reinforce immunity that is already present. Squalene-based adjuvant systems like AS03 and MF59 make it possible to reduce antigen content by half (to 7.5 µg) or three quarters (to 3.75 µg) without lowering the immunogenicity of the HA antigens, as measured by the titer of induced protective antibodies (9, 11). The large-scale use of pandemic H1N1 vaccines in Scandinavia and England was associated with an up to 17-fold increase in cases of narcolepsy in persons aged 4 to 18 who had received an AS03-adjuvanted vaccine (e12–e14). No such increase has yet been observed in connection with the MF59-adjuvanted pandemic vaccine (e15, e16), but the total number of children and adolescents vaccinated with this vaccine is too small for an association with narcolepsy to be definitively excluded. As for seasonal vaccines, clinical experience with the MF59 adjuvant system goes back many years. This is an oil-in-water emulsion based on squalene, which is a natural intermediate product of human endogenous cholesterol metabolism and a cellular Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47): 793–8
MEDICINE
TABLE 1 The properties and uses of approved influenza vaccines and those whose approval is pending*1 Properties*2 Whole-virus Split-virus vaccine vaccine Monovalent*2, inactivated
●
Subunit vaccine
Uses
EggCellbased*4 based*4
Adjuvanted
●
●
●
●
●
Trivalent* , inactivated
●
●
●
●
●
Quadrivalent, inactivated
●
2
Monovalent, live attenuated*
3
●
Virosomal
Seasonal
● ●
● ●
●
●
Trivalent, live attenuated
●
●
●
Quadrivalent, live attenuated*3
●
●
●
●
●
Trivalent, intradermal administration
●
Pandemic Pre-pandemic
●
*1 Modified from Pfleiderer M: Impfkolloquium Potsdam-Hermannswerder, 29–30 April 2011 *2 The product properties reflect combinations of different attributes, including the substrate for viral replication and other attributes; for example, split-virus vaccine/egg-based/adjuvanted, subunit vaccine/egg-based/virosomal, subunit vaccined/cell-based/adjuvanted, etc. For some of these combinations, e.g., split-virus vaccine/cell-based/virosomal, there is no approved product. 3 * Approved in the USA, but not in the EU 4 * Egg-based = replicated in incubated eggs; cell-based = replicated in cell culture
component. In Germany, an MF59-adjuvanted influenza vaccine (MF59-TIV) has been available since the 2000/2001 influenza season but is only approved for persons aged 65 and above. The vaccine is well tolerated aside from a somewhat higher frequency of local reactions, which are usually mild and of brief duration. Vaccination with MF59-TIV induces an immune response in elderly and/or chronically ill persons that is 1.2 to 1.8 times stronger than that induced by a non-adjuvanted TIV (10–12). The effect is particularly strong in persons who are both elderly and chronically ill, and in persons with a low antibody titer before vaccination (10, 11). Moreover, the vaccine induces immune response to influenza A strain variants (13, 14). Observational studies on the clinical efficacy of MF59-TIV have shown that vaccinated persons have a 68% to 87% relative risk reduction (compared to non-vaccinated persons) with respect to hospitalization for pneumonia, cerebrovascular accidents, or acute coronary syndrome (15, 16). In a further observational study on a cohort of persons aged 65 and above, MF59-TIV was found to lower the rate of hospitalization for influenza or pneumonia by 25% in comparison to TIV (17). Immunogenicity studies in children aged 6 months to or = 65 years (Fluzone High-Dose) and guidance for use – United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 485–6. 7. Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Ziegler T, Heikkinen T: Effectiveness of inactivated influenza vaccine in children aged 9 months to 3 years: an observational cohort study. Lancet Infect Dis 2011; 11: 23–9. 8. Song JY, Cheong HJ, Seo YB, et al.: Comparison of the long-term immunogenicity of two pandemic influenza A/H1N1 2009 vaccines, the MF59-adjuvanted and unadjuvanted vaccines, in adults. Clin Vaccine Immunol 2012; 19: 638–41. 9. Hatz C, von Sonnenburg F, Casula D, Lattanzi M, Leroux-Roels G: A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects. Vaccine 2012; 30: 70–7. 10. Podda A: The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine 2001; 19: 2673–80.
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11. Banzhoff A, Nacci P, Podda A: A new MF-59 adjuvanted vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis. Gerontology 2003; 49: 177–84. 12. Baldo V, Baldovin T, Floreani A, Carraro AM, Trivello R, Family Medicine Group of Pianiga: MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18–60 years of age) with chronic diseases who are at risk of post-influenza complications. Vaccine 2007; 25: 3955–61. 13. Del Giudice G, Hilbert AK, Bugarini R, et al.: An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine 2006; 24: 3063–5. 14. Baldo V, Baldovin T, Floreani A, Fragapane E, Trivello R: Response of influenza vaccines against heterovariant influenza virus strains in adults with chronic diseases. J Clin Immunol 2007; 27: 542–7. 15. Puig-Barberà J, Diez-Domingo J, Hoyos SP, Varea AB, Vidal DG: Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Vaccine 2004; 23: 283–9. 16. Puig-Barberà J, Díez-Domingo J, Varea AB, et al.: Effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. Vaccine 2007; 25: 7313–21. 17. Mannino S, Villa M, Apolone G, et al.: Effectiveness of adjuvanted influenza vaccination in elderly subjects in Northern Italy. Am J Epidemiol 2012; 176: 527–33. 18. Vesikari T, Pellegrini M, Karvonen A, et al.: Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant. Pediatr Infect Dis J 2009; 28: 563–71. 19. Vesikari T, Knuf M, Wutzler P, et al.: Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med 2011; 365: 1406–16. 20. Huckriede A, Bungener L, Stegmann T, et al.: The virosome concept for influenza vaccines. Vaccine 2005; 23: 26–38. 21. Conne P, Gauthey L, Vernet P, et al.: Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients. Vaccine 1997; 15: 1675–9. 22. de Bruijn IA, Nauta J, Gerez L, Palache A: Virosomal influenza vaccine: a safe and effective influenza vaccine with high efficacy in elderly and subjects with low pre-vaccination antibody titers. Virus Res 2004; 103: 139–45. 23. Herzog C, Metcalfe IC, Schaad UB: Virosome influenza vaccine in children. Vaccine 2002; 20: 24–8. 24. de Bruijn IA, Nauta J, Gerez L, Palache AM: The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad) in elderly subjects. Vaccine 2006; 24: 6629–31. 25. Baldo V, Baldovin T, Pellegrini M, et al.: Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol 2010: 517198. 26. Salleras L, Domínguez A, Pumarola T, et al.: Effectiveness of virosomal subunit influenza vaccine in preventing influenza-related illnesses and its social and economic consequences in children aged 3–14 years: a prospective cohort study. Vaccine 2006; 24: 6638–42. 27. van Damme P, Arnou R, Kafeja F, et al.: Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study. BMC Infect Dis 2010; 10: 134.
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28. Ansaldi F, Canepa P, Ceravolo A, et al.: Intanza(®) 15 mcg intradermal influenza vaccine elicits cross-reactive antibody responses against heterologous A(H3N2) influenza viruses. Vaccine 2012; 30: 2908–13. 29. Belshe RB, Gruber WC, Mendelman PM, et al.: Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. J Infect Dis 2000; 181: 1133–7. 30. Hoft DF, Babusis E, Worku S, et al.: Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis 2011; 204: 845–53. 31. Ashkenazi S, Vertruyen A, Arístegui J, et al.: CAIV-T Study Group. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Infect Dis J 2006; 118: 2298–312. 32. Fleming DM, Crovari P, Wahn U, et al.: Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J 2006; 25: 860–9. 33. Belshe RB, Edwards KM, Vesikari, et al.: Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007; 356: 685–96. 34. Belshe RB, Toback SL, Yi T, Ambrose CS: Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age. Influenza Other Respi Viruses 2010; 4: 141–5. 35. Osterholm MT, Kelley NS, Sommer A, Belongia EA: Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 36–44. 36. Ambrose CS, Wu X, Knuf M, Wutzler P: The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: A meta-analysis of 8 randomized controlled studies. Vaccine 2012; 30: 886–92. 37. Belshe RB, Gruber WC, Mendelman PM, et al.: Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 2000; 136: 168–75. 38. Block SL, Heikkinen T, Toback SL, Zheng W, Ambrose CS: The efficacy of live attenuated influenza vaccine against influenza-associated acute otitis media in children. Pediatr Infect Dis J 2011; 30: 203–7. 39. Belshe RB, Ambrose CS, Yi T: Safety and efficacy of live attenuated influenza vaccine in children 2–7 years of age. Vaccine 2008; 26: 10–6. 40. Hilleman MR: Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine 2002; 20: 3068–87. Corresponding author Prof. Dr. med. Peter Wutzler Universitätsklinikum Jena, Institut für Virologie und Antivirale Therapie Hans-Knöll-Str. 2 (Beutenberg Campus), D-07745 Jena, Germany [email protected]
@
For eReferences please refer to: www.aerzteblatt-international.de/ref4713
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47): 793–8
MEDICINE
REVIEW ARTICLE
Targeted Vaccine Selection in Influenza Vaccination Peter Wutzler, Roland Hardt, Markus Knuf, Klaus Wahle
eREFERENCES e1. Robert Koch-Institut: Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch-Institut/Stand: Juli 2012. Epidem Bull 2012/30. e2. Beyer WE, Palache AM, Osterhaus AD: Comparison of serology and reactogenicity between influenza subunit vaccines and whole virus or split vaccines: A review and meta-analysis of the literature. Clin Drug Investig 1998; 15: 1–12. e3. Anonymus: Erster Quadrivalenter Grippeimpfstoff. Dtsch Arztebl 2013; 110(12): A 569. (Pharmainformation) e4. Uphoff H, Hauri AM, Schweiger B, et al.: Zur Schätzung der Schutzwirkung der Influenzaimpfung aus Surveillancedaten. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2006; 49: 287–95. e5. Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V: Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2008; 2: CD004879. e6. Michiels B, Govaerts F, Remmen R, Vermeire E, Coenen S: A systematic review of the evidence on the effectiveness and risks of inactivated influenza vaccines in different target groups. Vaccine 2011; 29: 9159–70. e7. Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E: Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2010; 7: CD001269. e8. Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE: Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2010; 2: CD004876. e9. DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK: High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009–2010 season. Vaccine 2013; 31: 861–6. e10. Leroux-Roels I, Borkowski A, Vanwolleghem T, et al.: Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007; 370: 580–9 e11. Schwarz TF, Horacek T, Knuf M, et al.: Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 2009; 27: 6284–90. e12. Nohynek H, Jokinen J, Partinen M, et al.: AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhoodnarcolepsy in Finland. PLoS One 2012; 7: e33536. e13. Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al.:Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS ONE 2012; 7: e33723.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47) | Wutzler et al.: eReferences
e14. Miller E, Andrews N, Stellitano L, et al.: Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013; 346: 794. e15. Tsai TF, Crucitti A, Nacci P, et al.: Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011; 43: 702–6. e16. Choe YJ, Bae GR, Lee DH: No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. Vaccine 2012; 30: 7439–42. e17. Esposito S, Marchisio P, Montinaro V, et al.:The immunogenicity and safety of a single 0.5 mL dose of virosomal subunit influenza vaccine administered to unprimed children aged ≥ 6 to
REVIEW ARTICLE
Targeted Vaccine Selection in Influenza Vaccination Peter Wutzler, Roland Hardt, Markus Knuf, Klaus Wahle
SUMMARY Background: The main target groups for influenza vaccination are the elderly, the chronically ill, infants, and toddlers. Influenza vaccines are needed that suit the immunological particularities of each of these age and risk groups. Recent years have seen the approval of influenza vaccines that are more immunogenic than before, but whose use in Germany is limited by the restriction of reimbursement to a small number of vaccines. Methods: The Medline database was selectively searched for pertinent literature. Results: The suboptimal immunogenicity of conventional influenza vaccines that contain inactivated viral cleavage products and subunits can be markedly improved by the use of squalene-based adjuvant systems, by the integration of viral antigens in virosomal particles, or by intradermal administration. The vaccination of elderly persons with a vaccine containing the adjuvant MF59 was found to lower the risk of hospitalization for influenza or pneumonia by 25% compared to vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the adjuvant ASO3 was found to be associated with an up to 17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a virosomal vaccine lowered the frequency of laboratoryconfirmed influenza in vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%). Conclusion: The newer vaccines possess improved efficacy when used for primary and booster immunization in certain age and risk groups, and they are superior in this respect to conventional vaccines based on viral cleavage products and subunits. The risk/benefit profiles of all currently available vaccines vary depending on the age group or risk group in which they are used. ►Cite this as: Wutzler P, Hardt R, Knuf M, Wahle K: Targeted vaccine selection in influenza vaccination. Dtsch Arztebl Int 2013; 110(47): 793–8. DOI: 10.3238/arztebl.2013.0793
easonal influenza vaccination is recommended in Germany as a standard procedure for all persons aged 60 and above. Moreover, vaccination is also recommended for all persons at elevated risk of serious disease, for pregnant women, and for persons exposed to a higher than usual risk of infection (e1). In April 2012, the Strategic Advisory Group of Experts (SAGE) on Immunization of the World Health Organization (WHO) recommended the extension of national vaccination recommendations to children aged 6 to 59 months. Thus, the spectrum of target groups ranges from infants to very old persons, and from healthy persons with intact immune systems to the chronically ill. There is a corresponding variety in the tasks that influenza vaccines are required to fulfill. For example, a naive immune system that has never yet been in contact with influenza virus antigens cannot be effectively stimulated by the highly purified antigens contained in conventional influenza vaccines. The generation of robust immunity after primary vaccination requires a suitable vaccine, for example, one with added adjuvant or one containing live, attenuated virus (1). The elderly have a less effective immune system that has become accustomed to influenza virus antigens through decades of exposure to naturally occurring viruses and repeated immunizations. They therefore need a strong, age-specific immunologic stimulus to achieve lasting protection against disease due to infection with currently circulating influenza viruses. The same is true of influenza vaccines for the chronically ill. A number of influenza vaccines with improved immunogenicity have been approved in the last few years, and others are currently being clinically tested. In this article, we present the clinically relevant differences between conventional and newer influenza vaccines for each of the target groups in which they are used, and we discuss their optimal application.
S
Methods Institute of Virology and Antiviral Therapy – University Hospital Jena: Prof. Dr. med. habil. Wutzler Catholic Clinic Mainz, St. Hildegardis Hospital: Prof. Dr. med. Hardt Department of Child and Adolescent Medicine, Dr. Horst Schmidt Clinic GmbH, Wiesbaden: Prof. Dr. med. Knuf German Association of General Practitioners, Münster: Prof. Dr. med. Wahle
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47): 793–8
This review is based on a search in the Medline database for publications that appeared from January 2000 to February 2013 and that included the search terms “influenza vaccine,” “immunogenicity,” “efficacy,” and “effectiveness.” Particular emphasis was laid on randomized, controlled trials and meta-analyses.
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MEDICINE
Classes of vaccines The influenza viruses that are needed for antigen production in the manufacturing process of the currently approved seasonal, pandemic, and pre-pandemic vaccines are replicated either in incubated hen’s eggs (egg-based influenza vaccines) or in permanent cell lines (cell-based influenza vaccines, made with the use of Madin-Darby canine kidney cells [MDCK] or Vero simian kidney cells). These viruses for vaccination, once they have been inactivated with formaldehyde or β-propiolactone and then purified in a multistep process, can either be incorporated whole into a vaccine (whole-virus vaccines) or else used for the extraction of the viral hemagglutinin surface glycoprotein (HA). Depending on the intensity of the purification steps that follow, the final product is designated as either a splitvirus vaccine or a subunit vaccine (Table 1). Split-virus vaccines contain larger amounts of other viral components than subunit vaccines, which have been subjected to more intense purification. These additional components, however, are neither characterized nor quantified. The more intensely a viral preparation has been purified, the better tolerated it will be when administered, but at the cost of lower immunogenicity (e2). Both split-virus and subunit antigens can be incorporated in virosomal particles (virosomal influenza vaccines) or given in combination with adjuvant systems (adjuvanted influenza vaccines) (Table 1). Whole-virus vaccines are generally formulated without adjuvant. Seasonal trivalent inactivated vaccines (TIV) contain antigens of subtypes A/H1N1, A/H3N2, and B-strain. In Germany, in March 2013, the first quadrivalent inactivated vaccine (QIV) against influenza was approved, containing the HA antigens of the two different genetic lines of influenza B viruses (Victoria and Yamagata) (2, e3). Inactivated influenza vaccines for protection against zoonotic (“pre-pandemic”) or pandemic influenza viruses contain only the antigen of a single, relevant viral strain and are therefore called monovalent inactivated influenza vaccines. The alternative to inactivated vaccines is represented by live attenuated influenza vaccines (LAIV), which, like the inactivated vaccines, are produced in incubated eggs—in this case, in eggs that have been very thoroughly tested for contaminating foreign material (specific-pathogen-free or SPF eggs). LAIV have been approved in trivalent (EU, USA) and quadrivalent (USA) varieties. The efficacy of influenza vaccines depends to a large degree on the correspondence between the viral strains incorporated in the seasonal vaccine and the influenza viruses that are actually circulating during the current season (e4).
Vaccines with improved efficacy TIV with increased antigen content For healthy adults and older children, the efficacy of conventional TIV in the prevention of laboratoryconfirmed influenza infection is well documented (e5,
794
e6). Nonetheless, for persons at increased risk, elderly persons, and children under 8 years of age, the efficacy of these vaccines is moderate at best (e5–e8). For children under 2 years of age, a TIV was not found to be any more effective than placebo (e5). Multiple studies have shown that raising the antigen dose from 15 to 60 µg HA increases the immunogenicity of TIV, in the sense of elevating the concentration of antibodies measured in the hemagglutination inhibition test (3–5). On the other hand, the higher antigen dose is also associated with a higher frequency of moderate to severe local and systemic reactions, of which the most common types are pain (5% versus 0%) and myalgia (7% versus 1%) (4). A TIV of this type was approved in the USA in 2009 for use in persons aged 65 and above (6). A comprehensive phase IIIb trial of this high-dose vaccine was carried out during the 2009/2010 influenza season but did not yield any conclusion about its clinical efficacy, as the strain of virus for which the vaccine was designed was strongly divergent from the H1N1 pandemic virus that prevailed at that time (e9). It remains an open question whether the currently approved non-adjuvanted TIV with higher antigen doses are suitable for the primary immunization of immunologically naive persons. Evidence that this may be the case comes from a prospective cohort study carried out in Finland, where small children are given two adult doses of 15 µg HA at a 4-week interval for primary immunization (this is not the practice in other countries) (7). Adjuvanted trivalent influenza vaccines Extensive studies of candidate pandemic vaccines have clearly shown the superiority of adjuvanted vaccines over conventional ones for inducing immunity to the vaccine antigens (8, e10). This holds both for primary immunization of the naive immune system and for boosters to reinforce immunity that is already present. Squalene-based adjuvant systems like AS03 and MF59 make it possible to reduce antigen content by half (to 7.5 µg) or three quarters (to 3.75 µg) without lowering the immunogenicity of the HA antigens, as measured by the titer of induced protective antibodies (9, 11). The large-scale use of pandemic H1N1 vaccines in Scandinavia and England was associated with an up to 17-fold increase in cases of narcolepsy in persons aged 4 to 18 who had received an AS03-adjuvanted vaccine (e12–e14). No such increase has yet been observed in connection with the MF59-adjuvanted pandemic vaccine (e15, e16), but the total number of children and adolescents vaccinated with this vaccine is too small for an association with narcolepsy to be definitively excluded. As for seasonal vaccines, clinical experience with the MF59 adjuvant system goes back many years. This is an oil-in-water emulsion based on squalene, which is a natural intermediate product of human endogenous cholesterol metabolism and a cellular Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47): 793–8
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TABLE 1 The properties and uses of approved influenza vaccines and those whose approval is pending*1 Properties*2 Whole-virus Split-virus vaccine vaccine Monovalent*2, inactivated
●
Subunit vaccine
Uses
EggCellbased*4 based*4
Adjuvanted
●
●
●
●
●
Trivalent* , inactivated
●
●
●
●
●
Quadrivalent, inactivated
●
2
Monovalent, live attenuated*
3
●
Virosomal
Seasonal
● ●
● ●
●
●
Trivalent, live attenuated
●
●
●
Quadrivalent, live attenuated*3
●
●
●
●
●
Trivalent, intradermal administration
●
Pandemic Pre-pandemic
●
*1 Modified from Pfleiderer M: Impfkolloquium Potsdam-Hermannswerder, 29–30 April 2011 *2 The product properties reflect combinations of different attributes, including the substrate for viral replication and other attributes; for example, split-virus vaccine/egg-based/adjuvanted, subunit vaccine/egg-based/virosomal, subunit vaccined/cell-based/adjuvanted, etc. For some of these combinations, e.g., split-virus vaccine/cell-based/virosomal, there is no approved product. 3 * Approved in the USA, but not in the EU 4 * Egg-based = replicated in incubated eggs; cell-based = replicated in cell culture
component. In Germany, an MF59-adjuvanted influenza vaccine (MF59-TIV) has been available since the 2000/2001 influenza season but is only approved for persons aged 65 and above. The vaccine is well tolerated aside from a somewhat higher frequency of local reactions, which are usually mild and of brief duration. Vaccination with MF59-TIV induces an immune response in elderly and/or chronically ill persons that is 1.2 to 1.8 times stronger than that induced by a non-adjuvanted TIV (10–12). The effect is particularly strong in persons who are both elderly and chronically ill, and in persons with a low antibody titer before vaccination (10, 11). Moreover, the vaccine induces immune response to influenza A strain variants (13, 14). Observational studies on the clinical efficacy of MF59-TIV have shown that vaccinated persons have a 68% to 87% relative risk reduction (compared to non-vaccinated persons) with respect to hospitalization for pneumonia, cerebrovascular accidents, or acute coronary syndrome (15, 16). In a further observational study on a cohort of persons aged 65 and above, MF59-TIV was found to lower the rate of hospitalization for influenza or pneumonia by 25% in comparison to TIV (17). Immunogenicity studies in children aged 6 months to or = 65 years (Fluzone High-Dose) and guidance for use – United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 485–6. 7. Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Ziegler T, Heikkinen T: Effectiveness of inactivated influenza vaccine in children aged 9 months to 3 years: an observational cohort study. Lancet Infect Dis 2011; 11: 23–9. 8. Song JY, Cheong HJ, Seo YB, et al.: Comparison of the long-term immunogenicity of two pandemic influenza A/H1N1 2009 vaccines, the MF59-adjuvanted and unadjuvanted vaccines, in adults. Clin Vaccine Immunol 2012; 19: 638–41. 9. Hatz C, von Sonnenburg F, Casula D, Lattanzi M, Leroux-Roels G: A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects. Vaccine 2012; 30: 70–7. 10. Podda A: The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine 2001; 19: 2673–80.
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11. Banzhoff A, Nacci P, Podda A: A new MF-59 adjuvanted vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis. Gerontology 2003; 49: 177–84. 12. Baldo V, Baldovin T, Floreani A, Carraro AM, Trivello R, Family Medicine Group of Pianiga: MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18–60 years of age) with chronic diseases who are at risk of post-influenza complications. Vaccine 2007; 25: 3955–61. 13. Del Giudice G, Hilbert AK, Bugarini R, et al.: An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine 2006; 24: 3063–5. 14. Baldo V, Baldovin T, Floreani A, Fragapane E, Trivello R: Response of influenza vaccines against heterovariant influenza virus strains in adults with chronic diseases. J Clin Immunol 2007; 27: 542–7. 15. Puig-Barberà J, Diez-Domingo J, Hoyos SP, Varea AB, Vidal DG: Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Vaccine 2004; 23: 283–9. 16. Puig-Barberà J, Díez-Domingo J, Varea AB, et al.: Effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. Vaccine 2007; 25: 7313–21. 17. Mannino S, Villa M, Apolone G, et al.: Effectiveness of adjuvanted influenza vaccination in elderly subjects in Northern Italy. Am J Epidemiol 2012; 176: 527–33. 18. Vesikari T, Pellegrini M, Karvonen A, et al.: Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant. Pediatr Infect Dis J 2009; 28: 563–71. 19. Vesikari T, Knuf M, Wutzler P, et al.: Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med 2011; 365: 1406–16. 20. Huckriede A, Bungener L, Stegmann T, et al.: The virosome concept for influenza vaccines. Vaccine 2005; 23: 26–38. 21. Conne P, Gauthey L, Vernet P, et al.: Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients. Vaccine 1997; 15: 1675–9. 22. de Bruijn IA, Nauta J, Gerez L, Palache A: Virosomal influenza vaccine: a safe and effective influenza vaccine with high efficacy in elderly and subjects with low pre-vaccination antibody titers. Virus Res 2004; 103: 139–45. 23. Herzog C, Metcalfe IC, Schaad UB: Virosome influenza vaccine in children. Vaccine 2002; 20: 24–8. 24. de Bruijn IA, Nauta J, Gerez L, Palache AM: The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad) in elderly subjects. Vaccine 2006; 24: 6629–31. 25. Baldo V, Baldovin T, Pellegrini M, et al.: Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol 2010: 517198. 26. Salleras L, Domínguez A, Pumarola T, et al.: Effectiveness of virosomal subunit influenza vaccine in preventing influenza-related illnesses and its social and economic consequences in children aged 3–14 years: a prospective cohort study. Vaccine 2006; 24: 6638–42. 27. van Damme P, Arnou R, Kafeja F, et al.: Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study. BMC Infect Dis 2010; 10: 134.
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28. Ansaldi F, Canepa P, Ceravolo A, et al.: Intanza(®) 15 mcg intradermal influenza vaccine elicits cross-reactive antibody responses against heterologous A(H3N2) influenza viruses. Vaccine 2012; 30: 2908–13. 29. Belshe RB, Gruber WC, Mendelman PM, et al.: Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. J Infect Dis 2000; 181: 1133–7. 30. Hoft DF, Babusis E, Worku S, et al.: Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis 2011; 204: 845–53. 31. Ashkenazi S, Vertruyen A, Arístegui J, et al.: CAIV-T Study Group. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Infect Dis J 2006; 118: 2298–312. 32. Fleming DM, Crovari P, Wahn U, et al.: Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J 2006; 25: 860–9. 33. Belshe RB, Edwards KM, Vesikari, et al.: Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007; 356: 685–96. 34. Belshe RB, Toback SL, Yi T, Ambrose CS: Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age. Influenza Other Respi Viruses 2010; 4: 141–5. 35. Osterholm MT, Kelley NS, Sommer A, Belongia EA: Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 36–44. 36. Ambrose CS, Wu X, Knuf M, Wutzler P: The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: A meta-analysis of 8 randomized controlled studies. Vaccine 2012; 30: 886–92. 37. Belshe RB, Gruber WC, Mendelman PM, et al.: Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 2000; 136: 168–75. 38. Block SL, Heikkinen T, Toback SL, Zheng W, Ambrose CS: The efficacy of live attenuated influenza vaccine against influenza-associated acute otitis media in children. Pediatr Infect Dis J 2011; 30: 203–7. 39. Belshe RB, Ambrose CS, Yi T: Safety and efficacy of live attenuated influenza vaccine in children 2–7 years of age. Vaccine 2008; 26: 10–6. 40. Hilleman MR: Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine 2002; 20: 3068–87. Corresponding author Prof. Dr. med. Peter Wutzler Universitätsklinikum Jena, Institut für Virologie und Antivirale Therapie Hans-Knöll-Str. 2 (Beutenberg Campus), D-07745 Jena, Germany [email protected]
@
For eReferences please refer to: www.aerzteblatt-international.de/ref4713
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47): 793–8
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REVIEW ARTICLE
Targeted Vaccine Selection in Influenza Vaccination Peter Wutzler, Roland Hardt, Markus Knuf, Klaus Wahle
eREFERENCES e1. Robert Koch-Institut: Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch-Institut/Stand: Juli 2012. Epidem Bull 2012/30. e2. Beyer WE, Palache AM, Osterhaus AD: Comparison of serology and reactogenicity between influenza subunit vaccines and whole virus or split vaccines: A review and meta-analysis of the literature. Clin Drug Investig 1998; 15: 1–12. e3. Anonymus: Erster Quadrivalenter Grippeimpfstoff. Dtsch Arztebl 2013; 110(12): A 569. (Pharmainformation) e4. Uphoff H, Hauri AM, Schweiger B, et al.: Zur Schätzung der Schutzwirkung der Influenzaimpfung aus Surveillancedaten. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2006; 49: 287–95. e5. Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V: Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2008; 2: CD004879. e6. Michiels B, Govaerts F, Remmen R, Vermeire E, Coenen S: A systematic review of the evidence on the effectiveness and risks of inactivated influenza vaccines in different target groups. Vaccine 2011; 29: 9159–70. e7. Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E: Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev 2010; 7: CD001269. e8. Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE: Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2010; 2: CD004876. e9. DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK: High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009–2010 season. Vaccine 2013; 31: 861–6. e10. Leroux-Roels I, Borkowski A, Vanwolleghem T, et al.: Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007; 370: 580–9 e11. Schwarz TF, Horacek T, Knuf M, et al.: Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 2009; 27: 6284–90. e12. Nohynek H, Jokinen J, Partinen M, et al.: AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhoodnarcolepsy in Finland. PLoS One 2012; 7: e33536. e13. Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al.:Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS ONE 2012; 7: e33723.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2013; 110(47) | Wutzler et al.: eReferences
e14. Miller E, Andrews N, Stellitano L, et al.: Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013; 346: 794. e15. Tsai TF, Crucitti A, Nacci P, et al.: Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011; 43: 702–6. e16. Choe YJ, Bae GR, Lee DH: No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. Vaccine 2012; 30: 7439–42. e17. Esposito S, Marchisio P, Montinaro V, et al.:The immunogenicity and safety of a single 0.5 mL dose of virosomal subunit influenza vaccine administered to unprimed children aged ≥ 6 to
